Human Papillomavirus is a widespread pathogen that causes different types of warts, and is also the main cause of cervical cancer. In many patients, the immune system limits the spread of infection, but does not destroy the wart. Patients with deficient immune systems, or those taking immunosuppressants, have increased susceptibility to the spread of warts. Regression of warts can occur spontaneously or in response to some treatments, suggesting that under some circumstances, the immune system can cure the infection. We believe that the immune response is capable of presenting or eliminating HPV lesions. An understanding of the immune response against HPV that results in rejection or prevention of lesions is necessary to design vaccines that will prevent infection or induce the immune system to attack and destroy warts. In both cases, the prevention of long- term epithelial lesions should also prevent the higher rates of cancer that are associated with lesions induced by some strains of HPV. In this project, we will mount a comprehensive effort to understand the ways in which HPV interferes with the immune response in the skin (Project 1), the antigen specificity of the immune response against HPV (Project 2) and the type of immune mechanisms that are effective against HPV lesions (Project 3). This will lead to a more complete picture of the interplay between HPV and the immune system, allowing the rational design of two types of vaccine: protective vaccines that will prevent infection from becoming established or causing a skin lesion; and therapeutic vaccines that will be given to individuals who already have warts or cervical lesions, to cause regression of the lesions and reduce the risk of cancer.